There are a number of natural barriers that exist in living organisms. The barriers most likely developed over time as a mechanism to exclude harmful stimuli, such as toxic chemicals, from sensitive biochemical pathways. Cellular membranes, epithelial tissues and endothelial tissues are examples of such barriers.
Unfortunately, barriers such as cellular membranes function by excluding chemical compounds possessing particular physical characteristics rather than by specifically repelling harmful compositions. This can be problematic in the field of drug discovery where one is targeting a biopolymer encased in the barrier. Cellular membranes, for instance, are particularly intractable to highly charged compounds such as polynucleotides. When one administers a highly charged compound (e.g., oligonucleotide) to an organism, its medicinal utility is hindered by its inability to efficiently access its intracellular target.
Researchers have attempted to develop technologies for enhancing the transport of chemical compounds across organismal barriers. For instance, Ryser et al. discusses the use of high molecular weight lysine polymers for increasing the transport of various molecules across cellular membranes. See, Ryser, H. J. P., PCT Pub. No. WO 79/00515 (1979). Frankel et al. reports the conjugation of selected molecules to HIV tat protein, which increased cellular uptake of the molecules. See, Frankel et al, PCT Pub. No. WO 91/09958 (1991). Barsoum discusses the use of the HIV tat sequence RKKRRQRRR in (SEQ ID NO:1) in enhancing cellular membrane transport. See, Barsoum et al., PCT Pub. No. WO 94/04686 (1994). Brugidou et al. report the rapid internalization of a 16 amino acid peptide-cholesterol conjugate derived from the Antennapedia homeodomain by cultured neurons. See, Brugidou, J., et al. Biochem. Biophys. Res. Comm. 214(2):685-693 (1995).
Several methods have also been proposed to enhance the transport of compounds across epithelial tissues. For example, chemical enhancers (Burnette, R. R. In Developmental Issues and Research Initiatives; Hadgraft J., Ed., Marcel Dekker: 1989, pp. 247-288) and iontophoresis have been used for the transdermal transport of drugs. These efforts have produced fewer than a dozen drugs for transdermal administration.
More recently, methods and compositions have been described for transporting drugs and macromolecules across biological membranes in which the drug or macromolecule is covalently attached to a transport polymer consisting of from 6 to 25 subunits, at least 50% of which contain a guanidino or amidino side chain. The transport polymers are preferably polyarginine peptides composed of all D-, all L- or mixtures of D- and L-arginine subunits (see PCT/US/10571, WO/52614, published Nov. 26, 1998).
Despite the above, a need exists for new compositions and methods for enhancing the transport of compounds across biological barriers. The present invention fulfills this and other needs.